Process for the production of 4-[2&#39;, 6&#39;, 6&#39;-trimethylcyclohexen-(1&#39;)-yl]-2-methylbuten-(3)-al



United States Patent Claims. o. 260-598) This invention relates to thepreparation of 4-[2,6',6'- trimethylcyclohexen-(l)-yl] 2methylbuten-(3)-al-(l). More particularly, the present invention relatesto an improved procedure for producing 4-[2',6,6-trirnethylcyclohexen-(1')-yl]-2-methylbuten-(3)-al-(1) ofsignificantly greater purity and in markedly greater yields than knownheretofore.

One method for securing the desired aldehyde, suggested heretofore, maybe illustrated by the following reaction wherein R is a lower alkylradical and X is lithium, sodium or potassium.

The synthesis of the aldehyde (IV) in the aforesaid sequence is seen totake place in three separate steps. Thus, the oxido ester (II) isisolated and purified by vacuum distillation. The corresponding oxidoacid (III) obtained by saponification of the ester (II) is alsoseparated and, in the last step, converted presumably into the desired(Z -aldehyde (IV) by decarboxylation at an elevated temperature (i.e.,at least the boiling temperature of pyridine). Reference is made withregard to the aforesaid process of the prior art to Ishikawa, Chem.Zentralblatt, vol. II, p. 3452 (1937); N. Milas et al., J. Am. Chem.Soc., vol. 70, p. 1584 (1948); US. Patents 2,369,156; 2,369,160 until2,369,167.

It is noted that in the aforesaid reaction sequence, the sensitive anddesired intermediates are substantially destroyed or unattained. Thus,the method of isolation proposed and described by the discoverers (i.e.,Milas et a1. and Ishikawa et al.) of the aforesaid initially describedreaction sequence, recites the addition of water and acetic acid ortartaric acid to the primary condensation product, the oxido ester (11).This addition, it has now been established, leads, in fact, to thecomplete opening of the epoxy ring Thus, in attempting to isolate theoxido ester (II), hydroxy containing ester mixtures were actuallyformed, containing in preponderant amounts, theretro-a-hydroxycarboxylic acid ester of the formula:

wherein R is a lower alkyl radical corresponding to that of thechloroacetic acid alkyl ester of the initial condensation reaction asdescribed above. (See German Patent 1,080,- 550.) By saponification anddecar'ooxylation in the mannet of Ishikawa et a1. and Milas et al., thehydroxylated mixtures of reactants again yielded mixtures which, inturn, contained the product aldehyde, if at all, only in a very .lowstate of purity.

i It has been maintained by other and later workers in the field whoemployed the aforesaid process that the product secured by the aforesaidsequence is, in fact, not the product aldehyde (IV) but rather an isomerthereof of the formula:

As will be apparent the double bond of the side chain in the productaldehyde (VI) is present in the o e-position relative to the carbonylgroup of the aldehyde. Reference is thus made, with regard to thedescription of the aldehyde (VI) to Heiibron et al., J. Chem. Soc.(London), p. 727 (1942); p. 500 (1946); and p. 1516 (1949); H. H.Inhoifen et al., Liebigs Annalen, vol. 561, page 26 (1949); vol. 570, p.73 (1950); G. I. Samokhvalov et al., Journ. Gen. Chem. USSR, vol. 26, p.3457 (1956).

The production of this latter compound, the fi-C -aldehyde (VI) is alsodescribed by O. Isler in German Patent 842,190.

In the process of this reference, the condensation of fJ-ionone (I) iseffected by the method of Darzens employing a chloroacetic acid alkyl(i.e., ethyl) ester in the presence additionally of an alkali metalalcoholate, the reaction taking place at a reduced temperature withsaponification subsequently with an alkaline agent of the primarycondensation product without isolation thereof from the reactionmixture; and simultaneous decarboxylation to form, according to thedescription, B-C -aldehyde (VI). The latter product is, however,isolated from the reaction mixture by the addition of water.

Accordingly, it has now been discovered that the aidehyde, 4-[2,6',6trimethylcyclohexen (1')-yl]-2-methylbuten-(3)-al- (1), (IV), can beproduced in significantly high yields of substantial purity by theprocess that comprises reacting B-ionone with a chloroacetic acid alkylester, wherein the alkyl moiety is preferably a lower alkyl radical, byDargens method of condensation, at a reduced temperature in the presenceof a nucleophilic agent, such as an alkali metal alcoholate, alkalineearth metal alcoholate, alkali metal amide, alkali metal hydride, oramalgamated magnesium, and in the presence, optionally, of an inertorganic solvent. The resulting condensation product is treated in situwith an alkaline agent to effect saponification thereof and is alsoreacted with a substantially anhydrous acid reactant and sequentially,thereafter with water or an aqueous solution of an acidic agent, and thedesired aldehyde (IV) isolated from the reaction product mixture. 7

The instant process thus differs from the reaction sequence describedinitially above, that of Ishikawa et a1. and Milas et al., principally,in that the resulting very sensitive intermediate products are neitherisolated nor destroyed; the reaction is carried out at low temperaturesas a one vessel process and the product aldehyde (1V) is not onlyobtained, but, as indicated above, in high yields of substantial purity.

In contradistinction to the process of Isler et al., on the other hand,applicants obtain the desired aldehyde (IV) by a method wherein thesaponification is carried out by adding an alkaline agent and thefollowing decarboxylation by adding an acid agent, preferably anhydrous;and the aldehyde (IV) sequentially isolated from the reaction mixture towhich water or an aqueous of 1.2 to 2 mols thereof to each mol offl-ionone and preferably in a ratio of 1.5 to 1 respectively. The alkalimetal hydroxide is incorporated, for use, preferably in a 5 percent to20 percent (preferably 15 percent) alcoholic solution, most desirably anabsolute lower aliphatic alcohol, such as, for example, methanol orethanol. The reaction temperature depends on the concentration of thesaponification agent and lies preferably within the range of C. to 20 C.The period of saponification is from one hour to two hours.

The saponification product is then treated, preferably, as indicatedabove, without isolation thereof from the reaction mixture, with anexcess of an acid reagent, preferably, anhydrous, and at leastconcentrated; for example,

acid agent has been added after introduction therein of a lower fattyacid, containing from 1 to 6 carbon atoms, the anhydrous acid component.such as, formic acid, acetic acid or propionic acid, in

The result obtained according to the process of the insuch a manner thatthe temperature of the reaction mixvention is particularly surprising inview of the teaching of rule is maintained at not in excess of C. andnormally Heilbron et al., Inhotlen et al., Samokhvalov et al. alludednot below C. The reaction solution is thereafter to above who have evenrecently rejected the C -alde- 20 mixed with from 0.5 liter to 1.0 literof water or a like hyde (IV) as non-existent. volume of a dilute aqueousorganic acid or inorganic acid The following table indicates clearly thedistinctions solution, per mol of fl-ionone reactant initiallyintroduced, in properties of the desired product aldehyde, 4-[2',6,6'-and maintained at a temperature of between 0 C. andtrimethylcyclohexen-(l')-yl]-2 methylbuten (3) al- 30 C., and preferably20 C. Illustrative of the organic (1), (IV), from the isomeric aldehyde(VI). 25 acids which may be employed in the aforesaid aqueous TABLE IR,frequency in cm.-

Trans B.P., O./ n UV, km. Aldehyde Conjugated mm. Hg in m (a) H c=0 o=oo=o C14-aldehyde (IV) 82-84/007 1.4916 232 (5400) 1729 973 C14-aldehyde(VI) 78-80/0.03 1.5112 231 (17800) 1695 1640 Nucleus resonance spectraSemicarbazone Phenylsemi- Thiosemi- Proton M.P. in C. carbazonecarbazone Aldehyde proton signal number of M.P. in C. M.P. in 0.

double bonds (IV) split 2 122-124 120-121 112-113 (VI) simple 1 156-157181-182 195-196 For the production of the glycide ester (II), 1 mol ofsolution are dicarboxylic acids, and monoand di-hy- [R-ionone (I) iscondensed with 1.1-1.5, and preferably droxy substituted dicarboxylicacids, and preferably those 1.35, mols of a lower alkyl ester ofchloroacetic acid, for of 1 to 6 carbon atoms, such as oxalic acid andtartaric example, chloroacetic acid methyl ester or chloroacetic acid.Illustrative of the inorganic acids are sulfuric acid, acid ethyl ester,in the presence of 1.2-1.7, and preferably phosphoric acid, and thelike. These acids are employed, 1.5, mols of an alcohol-free alkalimetal alcoholate conif desired, in the dilute aqueous fonm, e.g., up to20 pertaining, preferably, from 1 to 6 carbon atoms, such as cent ofacid by volume, to produce a stronger degree of sodium methylate, sodiumethylate or potassium tert.- acidity in the aqueous phase. butylate, orof an alkaline earth metal alcoholate contain- The aqueous or acidicaqueous solution is added to ing, preferably, from 1 to 6 carbon atoms,amalgamated the reaction mixture at a temperature of 0 C. to 30 C.;magnesium, or an alkali metal amide or alkali metal hythe preferredtemperature being about 20 C. dride, at a temperature between 20 C. to10 C., and The isolation of the B-C -aldehyde (IV) takes placePreferably bfitween and in the Presence Q according to known methods,and is carried out prefer- Of a q inert Organic diluent, such pytetraably in an inert organic medium, such as an ether, e.g. y toluenethe llke- Preferably are diethyl ether or petroleum ether, wherein thedesired aldeused about 9 Parts to 200 Parts by Volume of dlluent hyde(IV) is dissolved. After purification of the organic mol of fi'lonone(I) employe? The of the phase for the removal of excess acid, there isobtained action depends on the condensatlon temperature and ls 6a theproduct, 4 [2,6,5, trimethy1cyc10heXen (1,) y1] 2 from 2 to 4 hours. Itis considered desirable that the methy1butn (3) a1 (1) (IV), as azresidue remaining aforesald reaction proceed 1n the presence of anantlft a or f0 f th 01v t Thi r duct oxidant, such as, for example,phenothiazine. or hydroer ev a I n O e 5 en S O 1 quinone, and with theexclusion of atmospheric oxygen then SLlbjCCtGd to lllgh vacuumdlstlllatlon for purlfica and moisture.

The glycide ester (II) thus obtained is not isolated The product'aldehydV valuable lnterpwqlate but is rather, ifi d in situ with an alkalineagent for the productlon of Vitamin A in accordance Wllh U .S. Thealkaline reagent employed is desirably an alkali metal Patent 2,567,572-hydroxide, for example, potassium hydroxide or sodium The followingexamples are further illustrative of the hydroxide. This saponificationreagent is used in a ratio invention.

Example 1 Into a mixture of 19.2 parts by weight of fi-ionone, 16.6parts by weight of chloroacetic acid ethyl ester, 0.1 part by weight ofphenothiazine and parts'by volume of absolute pyridine, are introducedat -10 C. to C., with the'exc-lusion of atmospheric oxygen and mQisture,8.1 parts by weight of alcohol-free sodium .methylate within a period often minutes. The reaction mixture is war-med to -5 0; this temperaturebeing maintained for tour hours. At the end of this period, 40.5 partsby volume of a 15 percent methanolic sodium hydroxide solution, producedby dissolving sodium hydroxide in absolute methanol, are addedand thereaction mixture left for 30 minutes at +10 C. At the expiration of thisperiod, the reaction mixture is then cooled to about 30 0, mixed with100 parts by weight of glacial acetic acid and subsequently, after theaddition of 100 parts by volume of water, left to stand for one hour.

The water-insoluble components are then extracted with low boilingpetroleum ether, the petroleum ether extract washed neutral with waterand dried over sodium sulfate. After evaporation of the ether in avacuum, the remaining crude aldehyde is purified by high vacuumdistillation.

There are'obtained 13.6 parts by weight (6.6 percent of the theoreticalof 4-(2,6',6'-trimethylcyc1ohexen-(1)-yl)- 2-methylbuten-(3)-a-l-(l) asan almost colorless liquid;

B.P. 82 C.84 C./0.07 mm. Hg; n 1.4916; :232 m 6:54am.

Analysis.C H O (M.W.=206.3). Calc.: C:

81.50%, H=10.75%. Found: C=81.16%, H:10.7l%.

The infra-red absorption spectrum shows at 1729 cm. the absorptioncharacteristics for the carbonyl oscillation of cap-saturated aldehydes,and at 973 cm. for the CH- oscillation of symmetrically disubstitutedtrans-CH=CH- ethylenes.

The nucleus resonance spectrum shows a resonance signal of the aldehydeproton split into two lines by the neighboring proton; as Well as twosignals which possess the characteristic chemical shift for protons ondouble bonds. Semicarbazone: M.P.= 122 C.-l24 C.; :230 m t (6 17.500).

Analysis.C H N G (M.W.=263.4). Calc.: C:

68.40%, H=9.57%, N=15.96%. Found C=68.63%,

Example 2 Into a mixture of 19.2 parts by weight of fl-ionone, 14.7parts by weight of chl-oroacetic acid methyl ester, 0.1 part by Weightof hydroquinone and 20 parts by volume of anhydrous tetrahyd-rofuran,there is introduced at l0 C. to -15 C., with the exclusion ofatmospheric oxygen and moisture, 10.2 parts by weight of alcohol-freesodium ethylene within a period of ten minutes. The reaction mixture ismaintained at 0 C. for one hour, 56 parts by volume of a 15 percentmethanolic potassium hydroxide solution produced by dissolving potassiumhydroxide in absolute methanol are subsequently allowed to run in andthe reaction mixture is maintained at 0 C. for one hour.

The reaction mixture is then cooled to about 3-0 0, mixed with 100 partsby volume of acetic acid and subsequently, after the addition of 100parts by volume of 10 percent aqueous tartaric acid, left to stand at+20 C. for one hour.

For the isolation of the aldehyde, the procedure is carried out as inExample 1; thepe'trol eum etherlbeing replaced by diethyl ether. 12.5parts by weight (61 percentof the theoretical) of an almost colorlessliquid with the same chemical and physical properties as'lthe substancedescribed in Example 1 are obtained. The product is 4-l2',6',6'-tri.methylcyclohexen-( 1" -y1l Z-methylbuten- )-a I What isclaimed is:

1. Process for the preparation of 4-[2',6,6'-trimethylcyclohexen-(1)-yl]-2-methy1buten(3 )-al-( 1) which comprises:

(a) reacting [i-ionone with an alkyl ester of chloroacetic acid, whereinthe alkyl moiety islower alkyl, at a temperature between-20 and 10 C.,inthe presence of a nucleophilic compound selected from the groupconsisting of an alkali metal al-coholate, an alkaline earth metalalcoholate, each of said alcoliolates having from 1 t'o 6'car b onatoms, amalgamated magnesium, an alkali metal amide and an alkali metalhydride, to for-ma condensation product of said fl-ionone and said alkylester of chloroacetic acid;

(b) adding an alkali hydroxide in situ while maintaining the temperaturebetween -10 and 20 C., whereby Isap'onific'a'tion of said condensationproduct is effected;

(c) treating the resulting product in situ with a lower aliphatic fattyacid while maintaining the temperature between 30 and 20 C.; and

(d) adding to the reaction mixture a member selected from the groupconsisting of water and a dilute acid while maintaining the mixturebetween 10 and 30 C.

2. Process for the preparation of 4-[2,6',6'-trimethy1- cyclohexen- 1'-yl] -.methy-lbuten-(3 -al-( 1) which comprises:

(a) reacting B-ionone with an alkyl ester of chloroacetic acid, whereinthe alkyl moiety is a lower alkyl of from 1 to 6 carbon atoms, at atemperature between 20 and 10 C., in the presence of a nucleophiliccompound selected from the group consisting of an alkali metalalcoholate, an alkaline earth metal alcoholate, each of said alcoholateshaving from 1 to 6 carbon atoms, amalgamated magnesium, an alkali metalamide and an alkali metal hydride to form a condensation product of said,B-ionone and said alkyl ester of ehloroacetic acid;

(b) adding an alkali metal hydroxide incorporated in a lower aliphaticalcohol solution in situ while maintaining the temperature between -l0and 20 C. to effect saponification of said condensation product;

(c) treating the resulting product in situ with an excess of asubstatially anhydrous acid selected from the group consisting of loweraliphatic fatty acids of from 1 to 6 carbon atoms while maintaining theternperature between 30 and 20 C.; and

(d) sequentially adding to the reaction mixture a member selected fromthe group consisting of water, dicarboxylic acids, monoanddihydroxydicarboxylic acids of from 1 to 6 carbon atoms, inorganicphosphoric acids and inorganic sulfuric acids, said acids being indilute aqueous solutions, while maintaining the mixture between 0 and 30C.

3. Process for the preparation of 4-[2',6,6-trimethylcyclohexen-( 1'-yll -2-methylbuten-(3 -al-( 1) which comprises:

(a) reacting fl-ionone with an alkyl ester of chloroacetic acid, whereinthe alkyl moiety is a lower alkyl of from 1 to 6 carbon atoms, in a molratio of l:1.1-l.5 and at a temperature of between 10 and 0 C. in thepresence of an inert organic diluent and 1.2 to 1.7 mols of anucleophilic compound selected from the group consisting of an alkalimetal alcoholate, an alkaline earth metal alcoholate, each of saidalcoholates having from 1 to 6 carbon atoms, amalgamated magnesium, analkali metal amide and an alkali metal hydride, to form a condensationproduct of said fl-ionone and said alkyl ester of chlo-roacetic acid;

(b) adding in situ an alkali metal hydroxide incorporated in a solutionof a lower aliphatic alcohol of from 1 to 4 carbon atoms, said hydroxidebeing added in amol ratio of 1.2 to 2 mols per mol of B-ionone, whilemaintaining the temperature between 10 and 20 to effect saponificationof said condensation product;

(c) treating the resulting product in situ with an excess of asubstantially anhydrous acid selected from the group consisting of loweraliphatic fatty acids of from 1 to 6 carbon atoms while maintaining thetemperature between 30 and 20 C.; and

(d) sequentially adding to the reaction mixture 0.5 to 1.0 liters permol of fl-ionone initially introduced of a member selected from thegroup consisting of water, dicarboxylic acids, mono-anddihydroxydicarboxylic acids of from 1 to 6 carbon atoms, inorganicphosphoric acids and inorganic sulfuric acids, said acids being indilute aqueous solution, while maintaining the mixture between 0 and 30C.

4. Process as claimed in claim 3 wherein the said ionone and said alkylester of chloroacetic acid are reacted initially in the presence ofsodium methylate.

5. Process as claimed in claim 3 wherein said alkyl ester ofchloroacetic acid is chloroacetic acid ethyl ester.

6. Process as claimed in claim 3 wherein said alkyl ester ofchloroacetic acid is chloroacetic acid methyl ester.

7. Process as claimed in claim 3 wherein the alkali metal hydroxide issodium hydroxide.

8. Process as claimed in claim 3 wherein the alkali metal hydroxide ispotassium hydroxide.

9. Process as claimed in claim 3 wherein the substantially anhydrousfatty acid is acetic acid.

10. Process as claimed in claim 3 wherein aqueous tartaric acid is addedin the last step.

References Cited by the Examiner UNITED STATES PATENTS 2,987,550 6/1961Stieg et al. 260--598 3,031,507 4/1962 Ortoli et a1. 260-598 OTHERREFERENCES Chemisches Zentralblatt, 1937, 11, p. 3452.

References Cited by the Applicant 1. M. Heilbrou, J. Chem. Soc 1942,727.

LEON ZITVER, Primary Examiner. I. I. SETELIK, .B. HELFIN, AssistantExaminers.

1. PROCESS FOR THE PREPARATION OF4-(2'',6'',6''-TRIMETHYLCYCLOHEXEN-(1'')-YL)-2-METHYLBUTEN-(3)-AL-(1)WHICH COMPRISES: (A) REACTION B-IONONE WITH AN ALKYL ESTER OFCHLOROACETIC ACID, WHEREIN THE ALKYL MOIETY IS LOWER ALKYL, AT ATEMPERATURE BETWEEN -20* AND 10*C., IN THE PRESENCE OF A NUCLEOPHILICCOMPOUND SELECTED FROM THE GROUP CONSISTING OF AN ALKALI METALALCOHOLATE, AN ALKALINE EARTH METAL ALCOHOLATE, EACH OF SAID ALCOHOLATESHAVING FROM 1 TO 6 CARBON ATOMS, AMALGAMATED MAGNESIUM, AN ALKALI METALAMIDE AND AN ALKALI METAL HYDRIDE, TO FORM A CONDENSATION PRODUCT OFSAID B-IONONE AND SAID ALKYL ESTER OF CHLOROACETIC ACID; (B) ADDING ANALKALI HYDROXIDE IN SITU WHILE MAINTAINING THE TEMPERATURE BETWEEN -10*AND 20*C., WHEREBY SAPONIFICATION OF SAID CONDENSATION PRODUCT ISEFFECTED; (C) TREATING THE RESULTING PRODUCT IN SITU WITH A LOWERALIPHATIC FATTY ACID WHILE MAINTAINING THE TEMPERATURE BETWEEN -30* AND20*C.; AND (D) ADDING TO THE REACTION MIXTURE A MEMBER SELECTED FROM THEGROUP CONSISTING OF WATER AND A DILUTE ACID WHILE MAINTAINING THEMIXTURE BETWEEN 0* AND 30*C.